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Optimizing Protection Against
Hepatitis A
Jossie M. Rogacion, MD,MSc., FPPS, FPSPGN
Associate Professor
University of the Philippines
College of Medicine
OUTLINE
• The virus
• The disease
• Prevention Strategies
– Improved sanitation
– Immunization
Hepatitis A Virus
• First described by Hippocrates in 5 B.C.
• 27 outbreaks in 17th-18th century
• Attacked Napoleon’s troops in 1799
• 1908: transmission via contaminated
food and water
• 1938 : hepatitis A virus isolated for the
first time
Hepatitis A Virus
• Naked RNA virus
• Related to enteroviruses, formerly known as enterovirus
72, now put in its own family: heptovirus
• One stable serotype only
• 6 genotypes exist, but in practice most are group 1
• Difficult to grow in cell culture: primary marmoset cell
culture and also in vivo in chimpanzees and marmosets
� Incubation period: Average 30 days
Range 15-50 days
� Jaundice by <6 yrs : <10%age group: 6-14 yrs: 40%-50%
>14 yrs : 70%-80%
� Complications: Fulminant hepatitisCholestatic hepatitisRelapsing hepatitis
� Chronic sequelae: None
Hepatitis A : The Disease
FecalHAV
Symptoms
0 1 2 3 4 5 6 12 24
Hepatitis A Infection
Total anti-HAV
Titre ALT
IgM anti-HAV
Months after exposure
Typical Serological Course
Hepatitis A Virus Transmission
EndemicityDisease
RatePeak Age
of Infection Transmission Patterns
High Low to High
Early childhood
Person to person;outbreaks uncommon
Moderate High Late childhood/
young adults
Person to person;food and waterborne outbreaks
Low Low Young adults Person to person;food and waterborne outbreaks
Very low Very low Adults Travelers; outbreaks uncommon
Global Patterns of
Hepatitis A Virus Transmission
Laboratory Diagnosis
• Acute infection is diagnosed by the detection of HAV-IgMin serum by EIA.
• Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.
• Cell culture – difficult and take up to 4 weeks, not routinely performed
• Direct Detection – EM, RT-PCR of faeces. Can detect illness earlier than serology but rarely performed.
• Many cases occur in community-wide outbreaks
– no risk factor identified for most cases
– highest attack rates in 5-14 year olds
– children serve as reservoir of infection
• Persons at increased risk of infection
– travelers
– homosexual men
– injecting drug users
Hepatitis A Vaccination Strategies
Epidemiologic Considerations
Why is there a need to protect against
Hepatitis A?
• Worldwide distribution:
– Estimated 1.5 Million cases per year
• Subclinical/asymptomatic in children BUT
severity increases with age:
– Relapsing
– Fulminant
– CFR > 50 years : 1.8 – 2.0%
– Overall mortality rate : 0.2 – 0.3%
Aetiology of acute hepatic failurePGH, 2000-2006
(n=26)Perc
enta
ge of childre
n (%)
Bravo LC. et al. Presented in WSPID
Congress, Argentina 2009
Laboratory tests for viral hepatitis
as measured by ELISA
Tests Results N (%)
Anti-HAV Test done
Positive*
Negative*
17 (65.4)
5 (29.4)
12 (70.6)
HBS antigen Test done
Positive*
Negative*
21 (80.8)
1 (4.8)†
20 (95.2)
Anti-Hep B core IgM Test done
Positive*
Negative*
4 (15.4)
1 (25)
3 (75)
Anti-Hep C virus Test done
Positive*
Negative*
5 (19.2)
1 (20.0)
4 (80.0)
*Note: Percentage of positive and negative subjects was calculatedbased on the number of subjects for whom the laboratory test was done.† One subject had positive result in hepatitis B surface antigen and antihepatitis B core IgM. Both positive results belong to the same subject. Bravo LC. et al. Presented in WSPID
Congress, Argentina 2009
Why is there a need to protect against
Hepatitis A?
• Direct and indirect costs of illness : economic burden especially in low-intermediate incidence areas ( high symptomatic adults)– U.S. 1997 : annual medical costs and costs of work-
loss > $480 million ( 63,363 symptomatic cases)
– Incidence decreasing over the years HOWEVER : in unvaccinated cases clinical characteristics remain the same, i.e. 73% had jaundice, 33% hospitalized, 0.3% died
– Hospitalization increases with age:• 22% in children < 5 years old
• 52% in > 60 years old
Optimal Protection Needed
• Depends on :
– Disease burden
• Level of endemicity
– Characteristics of host
• Age
• High-risk lifestyle
– Disease exposure
• None
• Positive exposure
Strategies for Optimal Protection
Immunization
+
Improved hygiene and sanitation
Worldwide distribution of hepatitis A
Intermediate 15-150
High > 150
Low 5-15
Very Low <5
WHO/Centers for Disease Control. 2008; Van Damme 2007 Endemicity based on Incidence/100,000
Age (years)Age (years)
Se
rop
rev
ale
nce
Se
rop
rev
ale
nce
of
an
tio
f a
nti
--
HA
V (
%)
HA
V (
%)
00
2020
4040
6060
8080
100100
10 20 30 40 5010 20 30 40 50
Improvement in Improvement in
hygienehygiene
Van Damme, 1994
Increase in Increase in
susceptiblessusceptibles
Prevalence changes related to
improvement in hygiene
Epidemiologic Shift
• shift in age of acquiring infection
from childhood to older age groups
World Prevalence of Anti-HAV antibodies
J. Infect Dis 1995: vol 171, Suppl1
Age-related anti-HAV prevalence in
Singapore
by decade,1975–95
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60
Age (years)
Pre
vale
nce (
%)
Chan (1975) Goh (1985) Fook (1995)
Age-related anti-HAV prevalence in
Thailand
Echeverria P, 1980; Poovorawan Y, 1990–1998.
An
ti-H
AV
%
0 2 4 6 8 10 12 14 16
Chon Buri 1990
Chumporn 1997
Songkla 1998
0
10
20
30
40
50
60
70
80
90
100
Nakornrajsima 1994
Nakornrajsima 1980
Age (years)
Age-group-specific prevalence of Anti-HAV in Filipinos living in / around Metro Manila, 1993
18.4
49.1
67.6
85.288.8 91.2
95.8
0
10
20
30
40
50
60
70
80
90
100
0-10 11-20 21-30 31-40 41-50 51-60 61 up
10-year age groups
Barzaga NG et al. Phil J Micro Infect Dis 1996; 25(2):39-47
% Prevalence
Seroepidemiology of Hepatitis A Virus Among Filipino
Children and Adults of Middle Income Families2004-2005 (N. Barzaga)
�Results: HAV seropositivity increases with age
� > 2 yo = 6%
� 2 - 15 yo = 28 – 34%
� 16 – 30 yo = 50 – 68%
� 31 – 40 yo = 73%
� 41 – 50 yo = 82%
� 51- 60 yo = 95%
HAV antibody % SeropositivityPhilippines, 1993 vs 2005
0-5 6-10 11-15 16-20 21-25 26-30 31-40 41-50 51-60 60++
Age Group in Years
1993: 62.3%
2005: 43.0%
Overall Anti-HAV antibody positivity in Metro Manila, Pampanga and Cebu City
was 42.3% - 43.3%; lower than 62% antibody positivity in MM in 1992 in
similar socioeconomic group
Seroepidemiology of Hepatitis A Virus Among Filipino
Children and Adults of Middle Income Families2004-2005 (N. Barzaga)
Conclusion:
– This changing pattern of HAV infection may reflect
improvements in the standard of living and
sanitation, a positive impact of hepatitis A
vaccination, and support universal vaccination of
young children
Role of Improving Sanitation and
Personal Hygiene
• an essential pre-requisite for the success of any HAV vaccination program
• Marked reduction in virus transmission in most developed countries came several decades ago due to improvement in living standards, better sanitation and environmental states in addition to higher income
• Same trend observed in several developing countries with increasing economic prosperity during the 1990s e.g., Singapore, Malaysia, Thailand and other South East Asian countries prior to vaccine era
Impact of Socioeconomic Status
on Prevalence : Philippine Experience
• Low vs. mid-upper
socioeconomic
status:
– Overall
seroprevalence
(n=202) = 47%
• Low income group
=67.6% vs. 26.5% in
mid-upper income
group
%
s
e
r
o
p
r
e
v
a
l
e
n
c
e
Diola B, et al. Presented in WSPID Congress 2003
• Pre-exposure
– Travelers to intermediate and high
HAV-endemic regions
• Post-exposure (within 14 days)Routine
– household and other intimate contacts
Selected situations
– institutions (e.g., day care centers)
– common source exposure (e.g., food prepared by infected food handler)
Hepatitis A Prevention - Immune
Globulin
Epidemiology
• one of the most widespread infections
transmitted via the fecal-oral route
• majority of subjects infected within 5 years of
age, usually asymptomatic thus acquiring life-
long immunity
• outbreaks and epidemics rare due to high
herd immunity level in the population
Epidemiology
• transmitted both by direct contact with
infected subjects and by ingestion of
contaminated food and drinks
• large epidemics or more limited outbreaks,
frequently starting in schools or day-care
centers can occur
• Incidence shows a cyclic pattern, with years of
peaks and years of troughs
Epidemiology
• In countries with low HAV endemicity :
– high hygienic standards substantially limit viral
spread
– outbreaks are rare
– hepatitis A is typically considered to be a
travellers’ infection
– subjects infected during travels abroad represent
a potential source of infection for others once
returned at home
Hepatitis A vaccine
• Developed in the late 1980’s
• Most are inactivated with a few live attenuated vaccines ( mostly in China)
• Strongly and rapidly immunogenic
• Since mid 1990’s : shift from 3 doses to two doses 6-18 months apart
• Minimal level of anti-HAV able to confer protection after vaccination has not been definitely established:
– Seroconversion : usually defined as the attainment of an antibody titer between 10 and 20 mIU/mL of anti-HAV
• For HAV protection :
– Both cellular and humoral immunity
– production of anti-HAV following active immunization:
• directly related to availability of neutralizing antibodies
• more importantly an indirect indication that immune memory has been established
– Consensus Statement ( Lancet 2003;362:165-71):
• vaccine elicit immune memory that persists even after loss of detectable antibodies
• rely more on immunologic memory rather than booster doses to protect vs. symptomatic disease
Commercially Available Vaccines
Vaccine Recipient’s
Age
Antigen
content
(strain)
Volume (ml) Doses (#) Schedule
(month)
Avaxim Pedia 12 mos. – 15
yrs. Inclusive
80 Ag units
(GBM)
0.5 2 0,6-12
Avaxim >15 yrs. 160 Ag units
(GBM)
0.5 2 0, 6-12
Epaxal ≥ 12 yrs. 24 IU (RG-SB) 0.5 2 0, 6-12
Havrix 720
Junior
12 mos. – 18
yrs. Inclusive
720 ELISA units
(HM175)
0.5 2 0, 6-12
Havrix 1440
Adult
> 18 yrs. 1440 ELISA
units (HM175)
1.0 2 0, 6-12
Vaqta
Pedia/Adol
formulation
12 mos. – 18
yrs. Inclusive
25 units (CR
326F)
0.5 2 0, 6-18
Vaqta Adult ≥ 19 yrs. 50 units (CR
326F)
1.0 2 0, 6-18
Hepatitis A vaccine:
Immunogenicity
• Seroconversion appears two weeks after a
single dose
• 95%–100% seroconvert 4 weeks after the first
vaccine administration
Werzberger et al 1992.N Engl J Med, 327:453–7;
Crovari et al 1992 . J Prev Med Hyg, 33:111–15;
Nalin et al 1993. J Hepatol, 18(suppl 2):S51–5;
Van Damme et al 1994. J Med Virol, 44:435–41
Studies on immunogenicity
• Following original three doses:
( Fan et al 1998. Vaccine, 16:232–5; Chan et al 1999. Vaccine,
17:369–72)
– long-term follow-up consistently showed 100%
seroconversion at month 7 (i.e., one month after
the last dose), when antibody titer also peaked
(GMTs of anti-HAV of 4133 and 3802 mIU/mL)
– all children in the two studies still anti-HAV
positive at month 60 of follow-up
Comparison of Immunogenicity
% se
roco
nve
rsion
Clinical Experience of AVAXIM 80u
Safety and Immunogenicity of a Pediatric Formulation of
Inactivated Hepatitis A Vaccine in Argentinean Children
Lopez et al, PIDJ 2001
Seroconversion rates and GMTs (mIU/ml) anti HAV
antibodies in seronegative subjects 12 – 47 months
given 2 doses of inactivated hepatitis A vaccine
Week 2Week 2 Week 4Week 4 After the boosterAfter the booster
99.1%99.1%
GMT
98.5
SE
RO
CO
NV
ER
SIO
N %
100 %100 % 100 %100 %
GMT
190GMT
6743
Studies on immunogenicity
• Antibody persistence:– up to 9 -12 years after immunization
(Wiens et al 1996. J Med Virol, 49:235–41; Werzberger et al 1998. N Engl J Med, 338:1160; 2002 Vaccine, 20:1699–701
Van Herck et al 2004. J Med Virol ,72:194-196)
• Mathematical models of antibody kinetics: – predict a persistence of anti-HAV at detectable level
for 14–30 years
– immune memory is expected to last much longer, making the need for booster doses later in life unlikely
(Van Damme et al 2003. Lancet, 362:1065–71)
Studies on immunogenicity
• Proof that immune memory already possible
after first dose:
– study based on the two-dose administration
schedule on children in Alaska
Williams et al 2000. Antiviral Ther, 13:5
• Delayed administration of second dose, with a mean
interval of 27 months, still resulted in seroconversion
to anti-HAV , although 17% of subjects were
seronegative before the booster dose
Hepatitis A vaccine:
Efficacy/Effectiveness
• Two studies performed using inactivated vaccines
(Vaqta™ and Havrix™) demonstrated the
excellent protection
1. Vaqta™ study :
• RCT ( vaccine vs. placebo), New York City community with
high Hep A incidence, n=1000 (2-16 yrs)
• Results : 34 hep A cases in placebo vs. 1 in vaccine grp
(already incubating on vaccination)
• Protective efficacy = 100% (lower limit of 95% CI = 87%)
Werzberger , et al. 1993. J Hepatol, 18(Suppl 2):S46–S50
Hepatitis A vaccine:
Efficacy/Effectiveness
2. Havrix™ study : evaluated effectiveness of two-
dose vaccine
– 40,000 Thai children in highly endemic
community
– Effectiveness was 94% (95% CI: 79%–99%)
Innis et al 1994. JAMA, 271:1328–34
Issues on active immunization
1. First 2 years of life : presence of maternal antibodies
– lower seroconversion rates and GMTs of anti-HAV were detected in infants born to seropositive vs. those born to seronegative mothers just after the completion of the vaccination course
– BUT : priming of immune memory occurs ,as demonstrated by the similar anamnestic response to a booster dose detected in subjects from both groups, independent of serological status of the mother
Piazza et al 1999 Vaccine, 17:585–8; Dagan et al 2000 Pediatr Infect Dis J, 19:1045–52; Fiore et al 2001. Proceedings of the 39th Annual Meeting of the Infectious Diseases Society of America
(IDSA); Oct 25–28, 2001)
Issues on active immunization
2. Flexibility of vaccine schedule
– Delayed second dose still showed anamnesticresponse to the second dose even as long as
2 – 5.5 yrs (Landry et al 2001); 4-6 yrs (Iwarson et al 2004); 20-31 months ( Williams et al 2003)
– Implication : persistence of immune memory for several years even after single dose
– HOWEVER: long-term protection after second dose observed when 2 doses administered so adhere with 2 doses
Issues on active immunization
3. Flexibility of vaccine use
– interchageability acceptable
WHO Recommendations for Hepatitis A
Vaccination According to Endemicity
Consider epidemiologic data and cost-benefit analyses before embarking on
national Hep A immunization policies.
ACIP Recommendations
• All children should receive hepatitis A vaccine at age1 year (i.e., 12–23 months), completed according to the licensed schedules and integrated into the routine childhood vaccination schedule.
• Children who are not vaccinated by age 2 years can be vaccinated at subsequent visits.
• In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children aged 2–18 years can be considered
Recommendations for Pre-exposure Immunoprophylaxis of
Hepatitis A for Travelers
AgeRecommended
ProphylaxisNotes
Younger than
12 monthsIG
0.02 ml/kg protects for up to 3 mo.
For trips of 3 mo or longer, 0.06 ml/kg
should be given at departure and every 5
mo if exposure to HAV continues.
12 mo
through 40 y
Hepatitis A
vaccine
41 y older
Hepatitis A
vaccine with or
without IG
If departure is in less than 2 wk, older
adults, immunocompromised people, and
people with chronic liver disease or other
chronic medical conditions can receive IG
with the initial dose of hepatitis A vaccine
to ensure optimal protection.
Recommendations for Post-exposure Immunoprophylaxis
of Hepatitis A
Time Since
ExposureAge of Patient Recommended Prophylaxis
2 wk or less
Younger than 12 mo
12 mo through 40 y
41 y or older
People of any age who
are
immunocompromised
or have chronic liver
disease
IG, 0.02 ml/kg
Hepatitis A vaccine
IG, 0.02 ml/kg, but hepatitis A vaccine can be used if IG is
unavailable
IG, 0.02 ml/kg
More than 2
wk
Younger than 12 mo
12 mo or older
No prophylaxis
No prophylaxis, but hepatitis A vaccine may be indicated
for ongoing exposure
Hepatitis A vaccine:
Safety
• After >188 million doses administered worldwide post registration (1992) and following a revision of data from different sources collected over 5 years:
– no serious adverse event was deemed to be causally related to hepatitis A vaccine
• Data of the US system of collection of adverse reactions following immunization (Vaccine Adverse Events Reporting System [VAERS]) :
– for those adverse reactions whose background incidence is known, rates reported in vaccinees are not higher than those found in unvaccinated subjects (CDC 1999).
Cost-Benefit Analysis of Routine Hepatitis A Immunization
Among Pre-School Children in a Developing Country
Rogacion JM
College of Medicine, University of the Philippines Manila
Summary: costs and benefits of
three strategies
Strategy Cost (PhP)
Benefit* (PhP)
Benefit-Cost (PhP)
No vaccination
3,834,420.27 18,667,128.69 14,832,708.62
Universal vaccination
26,917,800.00 6,152,640.00 -20,765,160.00
Screen and vaccinate
31,147,840.00 11,895,104.00 -19,252,736.00
* Foregone earnings from lost time of work and / or premature mortality due to fulminant hepatitis
Mass vaccination
Israel
– National coverage since July
1999
– Given at 18 and 24 months of
age
– Decline in cases from 50.4/
100,000 (ave. 1993-1998) to
2.2 – 2.5 / 100,000 ( 2002-
2004) : over 90% reduction
Dagan et al 2005. JAMA,294:202-210
SUMMARY
• Hepatitis A common but preventable disease.
• Incidence is affected by degree of sanitation.
• There is an changing pattern in
seroprevalence.
• Optimal protection can be achieved by
immunization AND improved hygiene and
sanitation
SUMMARY
• Available vaccines are highly immunogenic,
effective and safe.
• Universal vaccination may prove to be the
best strategy but needs to be correlated with
epidemiologic data.